Pulmonary hypertension (PH) is a disorder characterized by abnormally elevated pulmonary artery (PA) pressures and PH associated with chronic obstructive pulmonary disease (COPD) is highly prevalent, is associated increased morbidity and mortality, and lacks therapeutic options. Thus new pathways and therapeutic targets are needed to address this critical need. Recent work in our laboratory has identified the biologically active extracellular matrix fragment (matrikine) acetyl-proline-glycine-proline (AcPGP) as a key marker for COPD pathogenesis. PGP acts on inflammatory cells through CXC receptors (CXCR1/2) and signaling through the CXCR2 receptor has implications in PH development. We believe that the matrikine AcPGP causes pulmonary vasculopathy in COPD, leading to PH. We will test this hypothesis through the following independent but inter-related aims: 1. To determine the causative role for AcPGP-mediated signaling in models of PH 2. To elucidate mechanisms for matrikine-mediated pulmonary vascular remodeling 3. To evaluate the impact of matrikines on clinical features of COPD-PH This project explores new concepts in the pathobiology of COPD-PH through the use of novel animal models of PH, pulmonary vascular cell models, and applies these findings to a unique human cohort. The preclinical models tested will evaluate pathways and key therapeutic targets that could ultimately be tested in humans with COPD-PH. If successful, this project would provide the foundation by which these new therapies could be applied in a disease that currently has no treatment, potentially affecting the lives of patients affected with these devastating illnesses.